Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
Faculty of Chemistry and Chemical Biology, Technische Universität Dortmund, Germany.
Angew Chem Int Ed Engl. 2017 May 2;56(19):5363-5367. doi: 10.1002/anie.201701185. Epub 2017 Apr 11.
Skepinone-L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP-competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I1/2 binders for p38α MAP kinase. Type I1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X-ray crystallography.
Skepinone-L 最近被报道为一种具有高活性和优异选择性的 p38α MAP 激酶抑制剂，无论是在体外还是体内。然而，这类化合物仍然作为完全的 ATP 竞争性的 I 型结合物，此外，在酶上的停留时间很短。我们在此描述了 p38α MAP 激酶的进一步发展，即第一个 I 型/II 型结合物。I 型/II 型抑制剂干扰 R-螺旋，诱导甘氨酸翻转，并占据两个疏水区 I 和 II。这种设计方法导致靶标停留时间延长，与激酶的活性和非活性状态结合，具有极好的选择性、极好的酶水平抑制活性和在人全血测定中的纳摩尔级活性。这种有前途的结合模式通过 X 射线晶体学得到了证明。
